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Nuclear localization of proteasomes participates in stress-inducible resistance of solid tumor cells to topoisomerase II-directed drugs
Physiological cell conditions of solid tumors, such as glucose starvation and hypoxia,induce cellular resistance to topoisomerase II-directed drugs. Here, we show that the induction of drug resistance is mediated by nuclear accumulation of proteasomes, large multicatalytic protease complexes. We fou...
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| Published in: | Cancer research (Chicago, Ill.) Ill.), 2002-09, Vol.62 (17), p.5008-5012 |
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| container_end_page | 5012 |
| container_issue | 17 |
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| container_title | Cancer research (Chicago, Ill.) |
| container_volume | 62 |
| creator | OGISO, Yasunari TOMIDA, Akihiro TSURUO, Takashi |
| description | Physiological cell conditions of solid tumors, such as glucose starvation and hypoxia,induce cellular resistance to topoisomerase II-directed drugs. Here, we show that the induction of drug resistance is mediated by nuclear accumulation of proteasomes, large multicatalytic protease complexes. We found that the nuclear proteasome accumulation during glucose starvation was attenuated by stable expression of a mutant type of proteasome subunit, XAPC7, that lacked the nuclear localization signal (NLS). It is important that the expression of NLS-defective XAPC7 also diminished the induction of resistance to etoposide and doxorubicin, typical topoisomerase II-directed drugs. Under normal conditions, however, the NLS-defective XAPC7 had little effect on either nuclear proteasome distribution or etoposide sensitivity. Our findings demonstrate that stress-induced nuclear proteasome accumulation occurs through up-regulation of the NLS-dependent transport. Inhibition of the nuclear proteasome accumulation can be a novel approach to circumventing resistance to topoisomerase II-directed drugs. |
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Here, we show that the induction of drug resistance is mediated by nuclear accumulation of proteasomes, large multicatalytic protease complexes. We found that the nuclear proteasome accumulation during glucose starvation was attenuated by stable expression of a mutant type of proteasome subunit, XAPC7, that lacked the nuclear localization signal (NLS). It is important that the expression of NLS-defective XAPC7 also diminished the induction of resistance to etoposide and doxorubicin, typical topoisomerase II-directed drugs. Under normal conditions, however, the NLS-defective XAPC7 had little effect on either nuclear proteasome distribution or etoposide sensitivity. Our findings demonstrate that stress-induced nuclear proteasome accumulation occurs through up-regulation of the NLS-dependent transport. Inhibition of the nuclear proteasome accumulation can be a novel approach to circumventing resistance to topoisomerase II-directed drugs.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 12208754</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Antineoplastic agents ; Antineoplastic Agents, Phytogenic - pharmacology ; Biological and medical sciences ; Cell Cycle - drug effects ; Cell Division - drug effects ; Cell Nucleus - metabolism ; Chemotherapy ; Cysteine Endopeptidases - genetics ; Cysteine Endopeptidases - metabolism ; Cysteine Endopeptidases - physiology ; Doxorubicin - pharmacology ; Drug Resistance, Multiple - physiology ; Drug Resistance, Neoplasm ; Etoposide - pharmacology ; Glucose - deficiency ; HT29 Cells - drug effects ; HT29 Cells - metabolism ; HT29 Cells - physiology ; Humans ; Medical sciences ; Multienzyme Complexes - genetics ; Multienzyme Complexes - metabolism ; Multienzyme Complexes - physiology ; Nuclear Localization Signals - genetics ; Nuclear Localization Signals - physiology ; Pharmacology. Drug treatments ; Proteasome Endopeptidase Complex ; Stress, Physiological - metabolism ; Topoisomerase II Inhibitors ; Transfection ; Vincristine - pharmacology</subject><ispartof>Cancer research (Chicago, Ill.), 2002-09, Vol.62 (17), p.5008-5012</ispartof><rights>2003 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13884242$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12208754$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>OGISO, Yasunari</creatorcontrib><creatorcontrib>TOMIDA, Akihiro</creatorcontrib><creatorcontrib>TSURUO, Takashi</creatorcontrib><title>Nuclear localization of proteasomes participates in stress-inducible resistance of solid tumor cells to topoisomerase II-directed drugs</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Physiological cell conditions of solid tumors, such as glucose starvation and hypoxia,induce cellular resistance to topoisomerase II-directed drugs. Here, we show that the induction of drug resistance is mediated by nuclear accumulation of proteasomes, large multicatalytic protease complexes. We found that the nuclear proteasome accumulation during glucose starvation was attenuated by stable expression of a mutant type of proteasome subunit, XAPC7, that lacked the nuclear localization signal (NLS). It is important that the expression of NLS-defective XAPC7 also diminished the induction of resistance to etoposide and doxorubicin, typical topoisomerase II-directed drugs. Under normal conditions, however, the NLS-defective XAPC7 had little effect on either nuclear proteasome distribution or etoposide sensitivity. Our findings demonstrate that stress-induced nuclear proteasome accumulation occurs through up-regulation of the NLS-dependent transport. Inhibition of the nuclear proteasome accumulation can be a novel approach to circumventing resistance to topoisomerase II-directed drugs.</description><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Division - drug effects</subject><subject>Cell Nucleus - metabolism</subject><subject>Chemotherapy</subject><subject>Cysteine Endopeptidases - genetics</subject><subject>Cysteine Endopeptidases - metabolism</subject><subject>Cysteine Endopeptidases - physiology</subject><subject>Doxorubicin - pharmacology</subject><subject>Drug Resistance, Multiple - physiology</subject><subject>Drug Resistance, Neoplasm</subject><subject>Etoposide - pharmacology</subject><subject>Glucose - deficiency</subject><subject>HT29 Cells - drug effects</subject><subject>HT29 Cells - metabolism</subject><subject>HT29 Cells - physiology</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Multienzyme Complexes - genetics</subject><subject>Multienzyme Complexes - metabolism</subject><subject>Multienzyme Complexes - physiology</subject><subject>Nuclear Localization Signals - genetics</subject><subject>Nuclear Localization Signals - physiology</subject><subject>Pharmacology. Drug treatments</subject><subject>Proteasome Endopeptidase Complex</subject><subject>Stress, Physiological - metabolism</subject><subject>Topoisomerase II Inhibitors</subject><subject>Transfection</subject><subject>Vincristine - pharmacology</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNpFkN1KxDAQhYsouv68guRG7wpJmjbNpSz-LCx6o9fLbDLVSNvUTHqhL-Brm8UVYWA48M1hzjkoFqKu2lIrVR8WC855W9ZKy5PilOg9y1rw-rg4EVLyVtdqUXw_zrZHiKwPFnr_BcmHkYWOTTEkBAoDEpsgJm_9BCkLPzJKEYlKP7rZ-m2PLEtPCUaLu1MKvXcszUOIzGLfE0shzxT8zi4CIVutSucj2oSOuTi_0nlx1EFPeLHfZ8XL3e3z8qFcP92vljfr8k1qkUpXdcjBgeGqwwaVE1x3lXStNttGOC2EbToAJ1AZ54y11dbYpqqtVA1wY6qz4vrXN-f7mJHSZvC0exJGDDNttOS1MVpk8HIPztsB3WaKfoD4ufmrLgNXewAoV9fFHN_TP1e1rZJKVj8HD3yY</recordid><startdate>20020901</startdate><enddate>20020901</enddate><creator>OGISO, Yasunari</creator><creator>TOMIDA, Akihiro</creator><creator>TSURUO, Takashi</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20020901</creationdate><title>Nuclear localization of proteasomes participates in stress-inducible resistance of solid tumor cells to topoisomerase II-directed drugs</title><author>OGISO, Yasunari ; TOMIDA, Akihiro ; TSURUO, Takashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h271t-d3fe0ada904fe6e4d107f32d879b61d711c6faad1e49dd9cc3b9c635c246a0993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents, Phytogenic - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Division - drug effects</topic><topic>Cell Nucleus - metabolism</topic><topic>Chemotherapy</topic><topic>Cysteine Endopeptidases - genetics</topic><topic>Cysteine Endopeptidases - metabolism</topic><topic>Cysteine Endopeptidases - physiology</topic><topic>Doxorubicin - pharmacology</topic><topic>Drug Resistance, Multiple - physiology</topic><topic>Drug Resistance, Neoplasm</topic><topic>Etoposide - pharmacology</topic><topic>Glucose - deficiency</topic><topic>HT29 Cells - drug effects</topic><topic>HT29 Cells - metabolism</topic><topic>HT29 Cells - physiology</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Multienzyme Complexes - genetics</topic><topic>Multienzyme Complexes - metabolism</topic><topic>Multienzyme Complexes - physiology</topic><topic>Nuclear Localization Signals - genetics</topic><topic>Nuclear Localization Signals - physiology</topic><topic>Pharmacology. Drug treatments</topic><topic>Proteasome Endopeptidase Complex</topic><topic>Stress, Physiological - metabolism</topic><topic>Topoisomerase II Inhibitors</topic><topic>Transfection</topic><topic>Vincristine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>OGISO, Yasunari</creatorcontrib><creatorcontrib>TOMIDA, Akihiro</creatorcontrib><creatorcontrib>TSURUO, Takashi</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>OGISO, Yasunari</au><au>TOMIDA, Akihiro</au><au>TSURUO, Takashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nuclear localization of proteasomes participates in stress-inducible resistance of solid tumor cells to topoisomerase II-directed drugs</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2002-09-01</date><risdate>2002</risdate><volume>62</volume><issue>17</issue><spage>5008</spage><epage>5012</epage><pages>5008-5012</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Physiological cell conditions of solid tumors, such as glucose starvation and hypoxia,induce cellular resistance to topoisomerase II-directed drugs. Here, we show that the induction of drug resistance is mediated by nuclear accumulation of proteasomes, large multicatalytic protease complexes. We found that the nuclear proteasome accumulation during glucose starvation was attenuated by stable expression of a mutant type of proteasome subunit, XAPC7, that lacked the nuclear localization signal (NLS). It is important that the expression of NLS-defective XAPC7 also diminished the induction of resistance to etoposide and doxorubicin, typical topoisomerase II-directed drugs. Under normal conditions, however, the NLS-defective XAPC7 had little effect on either nuclear proteasome distribution or etoposide sensitivity. Our findings demonstrate that stress-induced nuclear proteasome accumulation occurs through up-regulation of the NLS-dependent transport. Inhibition of the nuclear proteasome accumulation can be a novel approach to circumventing resistance to topoisomerase II-directed drugs.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>12208754</pmid><tpages>5</tpages></addata></record> |
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| subjects | Antineoplastic agents Antineoplastic Agents, Phytogenic - pharmacology Biological and medical sciences Cell Cycle - drug effects Cell Division - drug effects Cell Nucleus - metabolism Chemotherapy Cysteine Endopeptidases - genetics Cysteine Endopeptidases - metabolism Cysteine Endopeptidases - physiology Doxorubicin - pharmacology Drug Resistance, Multiple - physiology Drug Resistance, Neoplasm Etoposide - pharmacology Glucose - deficiency HT29 Cells - drug effects HT29 Cells - metabolism HT29 Cells - physiology Humans Medical sciences Multienzyme Complexes - genetics Multienzyme Complexes - metabolism Multienzyme Complexes - physiology Nuclear Localization Signals - genetics Nuclear Localization Signals - physiology Pharmacology. Drug treatments Proteasome Endopeptidase Complex Stress, Physiological - metabolism Topoisomerase II Inhibitors Transfection Vincristine - pharmacology |
| title | Nuclear localization of proteasomes participates in stress-inducible resistance of solid tumor cells to topoisomerase II-directed drugs |
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